The US Food and Drug Administration has approved dextromethorphan hydrobromide and bupropion hydrochloride extended-release tablets (Auvelity) for the treatment of agitation associated with dementia due to Alzheimer’s disease, according to a press release from Axsome Therapeutics.

Agitation is reported in up to 76% of patients with Alzheimer’s disease and may include emotional distress, disruptive irritability, disinhibition, and verbal or physical aggression. Alzheimer’s disease affects more than 7 million people in the US.

The approval was supported by a clinical development program that included randomized, double-blind phase 3 studies and long-term safety data. In the 5-week ADVANCE-1 trial, dextromethorphan-bupropion was associated with statistically significant improvement compared with placebo in agitation symptoms, measured by change in Cohen-Mansfield Agitation Inventory total score at week 5. A statistically significantly greater proportion of treated patients also were rated by clinicians as at least minimally improved on the modified Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change.

In ACCORD-2, a long-term randomized withdrawal trial, patients who had responded to dextromethorphan-bupropion were randomly assigned to continue treatment or switch to placebo for up to 6 months. Patients who continued treatment had a statistically significantly longer time to relapse of agitation symptoms than those who switched to placebo. Because the trial enrolled known responders before randomization, the relapse findings should be interpreted in that context.

Dextromethorphan is thought to act on N-methyl-D-aspartate and sigma-1 receptors. The bupropion component inhibits cytochrome P450 2D6, increasing dextromethorphan exposure. However, the exact mechanism of action in agitation associated with dementia due to Alzheimer’s disease is unclear.

For agitation associated with Alzheimer’s disease, the recommended dosing differs from the regimen used for major depressive disorder. Dosing is initiated at 30 mg/105 mg (dextromethorphan/bupropion) once daily for 7 days, increased to twice daily on day 8, and then increased to 45 mg/105 mg twice daily from day 15 based on tolerability. Clinicians should also be aware that bupropion’s inhibition of CYP2D6 may affect the metabolism of other CYP2D6-metabolized drugs; concomitant use of monoamine oxidase inhibitors is contraindicated. Prescribers should consult the full prescribing information for a complete list of interactions and contraindications.

In the ADVANCE-1 trial, the most common adverse reactions occurring in at least 5% of treated patients and more than twice as often as placebo were dizziness and dyspepsia. Discontinuation due to adverse events occurred in 1.3% of patients receiving dextromethorphan-bupropion, the same rate reported with placebo.

The prescribing information includes a boxed warning for suicidal thoughts and behaviors associated with antidepressants. Other clinically relevant risks include seizures, increased blood pressure, dizziness and fall risk, serotonin syndrome, angle-closure glaucoma, mania, unusual thoughts or behaviors, and hyponatremia, which may be more pronounced in older adults. Dextromethorphan-bupropion should not be used as an as-needed treatment for agitation associated with dementia due to Alzheimer’s disease.

Dextromethorphan-bupropion was previously approved for major depressive disorder in adults. The agitation indication was developed with FDA Breakthrough Therapy designation and reviewed under Priority Review.

Source: Axsome Therapeutics